rs2273346

Variant names:

• chr1-11030840-A-G
• rs2273346
• NM_006610.4:c.1130T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006610.4(MASP2):​c.1130T>C​(p.Val377Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0336 in 1,613,664 control chromosomes in the GnomAD database, including 2,381 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (551 hom., cov: 32)
  • Exomes 𝑓: 0.031 (1830 hom.)
• Consequence: MASP2 NM_006610.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.97
• Publications: 40 publications found

Genes affected

MASP2 (HGNC:6902): (MBL associated serine protease 2) This gene encodes a member of the peptidase S1 family of serine proteases. The encoded preproprotein is proteolytically processed to generate A and B chains that heterodimerize to form the mature protease. This protease cleaves complement components C2 and C4 in order to generate C3 convertase in the lectin pathway of the complement system. The encoded protease also plays a role in the coagulation cascade through cleavage of prothrombin to form thrombin. Myocardial infarction and acute stroke patients exhibit reduced serum concentrations of the encoded protein. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Feb 2016]

MASP2 Gene-Disease associations (from GenCC):

• immunodeficiency due to MASP-2 deficiency

  Inheritance: AR Classification: STRONG Submitted by: Laboratory for Molecular Medicine

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020970702).
• BP6: Variant 1-11030840-A-G is Benign according to our data. Variant chr1-11030840-A-G is described in ClinVar as Benign. ClinVar VariationId is 291785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.195 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MASP2	NM_006610.4	c.1130T>C	p.Val377Ala	missense_variant	Exon 9 of 11	ENST00000400897.8	NP_006601.2
MASP2	XR_001736931.1	n.1083T>C		non_coding_transcript_exon_variant	Exon 8 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MASP2	ENST00000400897.8	c.1130T>C	p.Val377Ala	missense_variant	Exon 9 of 11	1	NM_006610.4	ENSP00000383690.3

Frequencies

GnomAD3 genomes AF: 0.0600 AC: 9126 AN: 152018 Hom.: 550 Cov.: 32

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0365

Gnomad ASJ AF: 0.0349

Gnomad EAS AF: 0.206

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.00999

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0190

Gnomad OTH AF: 0.0632

GnomAD2 exomes AF: 0.0502 AC: 12612 AN: 251006 AF XY: 0.0504

Gnomad AFR exome AF: 0.130

Gnomad AMR exome AF: 0.0229

Gnomad ASJ exome AF: 0.0403

Gnomad EAS exome AF: 0.210

Gnomad FIN exome AF: 0.0103

Gnomad NFE exome AF: 0.0188

Gnomad OTH exome AF: 0.0402

GnomAD4 exome AF: 0.0308 AC: 45045 AN: 1461528 Hom.: 1830 Cov.: 30 AF XY: 0.0325 AC XY: 23642 AN XY: 727080

African (AFR) AF: 0.126 AC: 4220 AN: 33454

American (AMR) AF: 0.0242 AC: 1081 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.0431 AC: 1127 AN: 26122

East Asian (EAS) AF: 0.191 AC: 7576 AN: 39664

South Asian (SAS) AF: 0.0921 AC: 7939 AN: 86192

European-Finnish (FIN) AF: 0.00975 AC: 521 AN: 53414

Middle Eastern (MID) AF: 0.0516 AC: 297 AN: 5754

European-Non Finnish (NFE) AF: 0.0176 AC: 19535 AN: 1111864

Other (OTH) AF: 0.0455 AC: 2749 AN: 60386

GnomAD4 genome AF: 0.0601 AC: 9148 AN: 152136 Hom.: 551 Cov.: 32 AF XY: 0.0613 AC XY: 4562 AN XY: 74386

African (AFR) AF: 0.129 AC: 5366 AN: 41474

American (AMR) AF: 0.0364 AC: 555 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0349 AC: 121 AN: 3470

East Asian (EAS) AF: 0.205 AC: 1057 AN: 5160

South Asian (SAS) AF: 0.101 AC: 485 AN: 4822

European-Finnish (FIN) AF: 0.00999 AC: 106 AN: 10614

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0190 AC: 1290 AN: 68010

Other (OTH) AF: 0.0634 AC: 134 AN: 2112

Alfa AF: 0.0338 Hom.: 883

Bravo AF: 0.0642

TwinsUK AF: 0.0210 AC: 78

ALSPAC AF: 0.0200 AC: 77

ESP6500AA AF: 0.128 AC: 564

ESP6500EA AF: 0.0181 AC: 156

ExAC AF: 0.0528 AC: 6413

Asia WGS AF: 0.133 AC: 460 AN: 3478

EpiCase AF: 0.0229

EpiControl AF: 0.0238

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency due to MASP-2 deficiency Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	12
DANN	Benign	0.79
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.0
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.15
Sift	Benign	0.051	T
Sift4G	Benign	0.081	T
Polyphen		0.0020	B
Vest4		0.044
MPC		0.048
ClinPred		0.012	T
GERP RS		2.8
Varity_R		0.32
gMVP		0.27
Mutation Taster		=89/11	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2273346; hg19: chr1-11090897; COSMIC: COSV68896553; COSMIC: COSV68896553;